Epstein-Barr virus (EBV) is the etiologic agent of classical infectious mononucleosis. Its property of inducing cell transformation and its association with human neoplasms makes the study of this virus of prime importance. Although the intense lymphoproliferation that occurs in infectious mononucleosis resembles the acute phase of leukemia, the former disease is always or almost always self-limiting and benign. This self-limitation in vivo is in direct contrast to the capacity of the patient's lymphocytes to proliferate indefinitely in vitro with surface characteristics typical for B lymphocytes. The main objective of this study is to further define the mechanism responsible for the self-limited feature of lymphoproliferation in patients with EBV induced infectious mononucleosis. Patients with EBV associated infectious mononucleosis and their family contacts are serially examined for lymphocyte subpopulation changes. The latter findings are associated with age, clinical manifestations, antibody response to antigens of EBV, and EBV excretion of the study participants. Our initial results have demonstrated that adult patients with infectious mononucleosis develop a transient reduction in the number of IgM and IgG bearing lymphocytes in the early phase of the disease. A similar finding has been recently noted, although less consistently, in adults with other forms of primary or in reactivated EBV infections. A nearly opposite phenomenon has been noted in very young patients with this disease and who lack a heterophile antibody response. Our initial results have also shown that surveillance of families of acute cases of infectious mononucleosis results in a high yield of individuals experiencing acute EBV infections. However, larger number of study individuals are needed to corroborate and expand the initial findings. Studying the host's immune responses to the various forms of EBV infections can provide an important framework for future research regarding the functional interaction between EBV and B lymphocytes. Our findings also have a potential for identifying important interrelationships between normal lymphocyte reactions and cancerous ones.